Benzisoxazole piperidinyl derivatives, pharmaceutical compositions comprising the derivatives and their use

Abstract

The invention relates to a benzisoxazolyl piperidine derivative having the following general formula, a salt or a hydrate thereof, wherein R, X, Y, R′ and T are defined as in the specification. Such compounds have serotonin system modulating effects such as antagonizing effect on 5-HT 2A and inhibitory effect on 5-HT reuptake. The compounds have good analgesic and sedative activities with mild toxic and side effects. The invention also relates to a composition comprising said derivative and the use thereof.

1 . A benzisoxazolyl piperidine derivative having the following general formula, and a salt or a hydrate thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R represents H, halogen, unsubstituted or halogen-substituted C 1 -C 4  alkyl or unsubstituted or halogen substituted C 1 -C 4  alkoxy; 
 X and Y represent independently CH or N; 
 R′ represents H, halogen, cyano, C 1 -C 4  alkyl unsubstituted or substituted with halogen or cyano, C 1 -C 4  alkoxy unsubstituted or substituted with halogen or cyano, or —C(═O)R 1 , wherein R 1  represents H, C 1 -C 4  alkyl or C 1 -C 4  alkoxy; and 
 T represents a saturated or unsaturated, linear or branched carbon chain linking group having 1-10 carbon atoms, wherein any carbon atom of the carbon chain linking group can be replaced with one or more oxygen or sulfur atoms. 
 
     
     
         2 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein R represents H, halogen, or C 1 -C 4  alkoxy, preferably H, F or OCH 3 . 
     
     
         3 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein R′ represents H, halogen, cyano or —C(═O)R 1 , wherein R 1  represents H, C 1 -C 4  alkyl or C 1 -C 4  alkoxy. 
     
     
         4 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein R′ represents H, Cl, F, CN or COOCH 3 . 
     
     
         5 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein T represents a saturated, linear or branched carbon chain linking group having 2-7 carbon atoms, wherein any carbon atom of the carbon chain linking group can be replaced with one or more oxygen or sulfur atoms, preferably with one or two oxygen or sulfur atoms. 
     
     
         6 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein the salt is hydrochloride, hydrobromide, sulfate, trifluoroacetate or methanesulfonate, preferably hydrochlorid or hydrobromide. 
     
     
         7 . The benzisoxazolyl piperidine derivative according to  claim 1 , wherein the salt contains 0.5-3 molecules of crystal water. 
     
     
         8 . The benzisoxazolyl piperidine derivative according to  claim 1 , being a compound selected from the group consisting of
 3-(1-(2-(1H-indol-1-yl)ethyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(3-(1H-indol-1-yl)propyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(4-(1H-indol-1-yl)butyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(5-(1H-indol-1-yl)pentyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   6-fluoro-3-(1-(3-(6-fluoro-1H-indol-1-yl)propyl)piperidin-4-yl)benzo[d]isoxazole,   1-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)-1H-indole-6-carbonitrile,   methyl 1-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propyl)-1H-indole-6-carboxylate,   6-fluoro-3-(1-(4-(6-fluoro-1H-indol-1-yl)butyl)piperidin-4-yl)benzo[d]isoxazole,   1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-1H-indole-6-carbonitrile,   3-(1-(4-(6-chloro-1H-indol-1-yl)butyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(3-(1H-benzo[d]imidazol-1-yl)propyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(4-(1H-benzo[d]imidazol-1-yl)butyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   3-(1-(3-(1H-indazol-1-yl)propyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-1H-indazole-6-carbonitrile,   1-(4-(4-(benzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-1H-indole-6-carbonitrile,   6-fluoro-3-(1-(3-(6-fluoro-1H-benzo[d]imidazol-1-yl)propyl)piperidin-4-yl)benzo[d]isoxazole,   6-fluoro-3-(1-(4-(6-fluoro-1H-benzo[d]imidazol-1-yl)butyl)piperidin-4-yl)benzo[d]isoxazole,   1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-1H-benzo[d]imidazole-6-carbonitrile,   1-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethoxy)-1H-indole-6-carbonitrile,   1-(3-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)propoxy)-1H-indole-6-carbonitrile,   3-(1-(2-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yloxy)ethyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole, or   3-(1-(3-(6-chloro-1H-benzo[d][1,2,3]triazol-1-yloxy)propyl)piperidin-4-yl)-6-fluorobenzo[d]isoxazole,   
       or a salt or a hydrate thereof. 
     
     
         9 . The benzisoxazolyl piperidine derivative according to  claim 8 , the derivative being a compound selected from the group consisting of
 6-fluoro-3-(1-(4-(6-fluoro-1H-indol-1-yl)butyl)piperidin-4-yl)benzo[d]isoxazole,   1-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)butyl)-1H-indole-6-carbonitrile, or   6-fluoro-3-(1-(4-(6-fluoro-1H-benzo[d]imidazol-1-yl)butyl)piperidin-4-yl)benzo[d]isoxazole,   
       or a salt or a hydrate thereof. 
     
     
         10 . A pharmaceutical composition comprising a therapeutically effective amount of a benzisoxazolyl piperidine derivative according to  claim 1 , a salt or a hydrate thereof, and a pharmaceutically acceptable carrier. 
     
     
         11 . Use of a benzisoxazolyl piperidine derivative according to  claim 1  in the preparation of analgesics and sedatives for the treatment of pains. 
     
     
         12 . The use according to  claim 11 , wherein the pains include nociceptive pain, acute pain, chronic pain, neuropathic pain, psychogenic pain and mixed pain. 
     
     
         13 . A method of treating pains in mammals, comprising administering a benzisoxazolyl piperidine derivative according to  claim 1 , a salt or a hydrate thereof to an individual with such need. 
     
     
         14 . The method according to  claim 13 , wherein the pains include nociceptive pain, acute pain, chronic pain, neuropathic pain, psychogenic pain and mixed pain.